[Crystalline polymorphism of eflucimibe]. / Polymorphisme cristallin de l'éflucimibe.

The importance, in therapeutics, of the concept of bioavailability and on-going quality research in the formulation of a drug has prompted us to examine the crystalline polymorphism of eflucimibe as from the research phase. This study has been carried out by re-crystallization of the product in organic solvents having a different polarity in a variety of experimental temperature and pressure conditions, then, subsequently, by re-cooling the previously dissolved substance. The analytical methods applied to identify and then describe the polymorphic forms are thermogravimetry analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction from synchrotron radiation (XRPD), infrared spectrometry (IR), solid-state nuclear magnetic resonance spectrometry (SSNMR) and lastly maximum solubility measurements. By means of XRPD, two polymorphic forms called A and B have been clearly identified at ambient temperature. These two crystalline forms were obtained in a reproducible way, then described by DSC, XRPD, IR and SSNMR. Differential scanning calorimetry analysis has shown for polymorphic form A two endothermic phenomena with low energy at about 35 masculine and 118 degrees C attributed by XRDP to conformational polymorphism. The complex endothermic event that extends between 75 masculine and 105 degrees C appears to correspond to successive alterations of a lamellar structure. The solid-solid transition observed at 110 degrees C is due to a change of crystalline phase, then the melting point occurring at about 130 degrees C. For form B, two changes of crystalline phase are clearly observed at about 80 masculine and 120 degrees C. The reversibility of these changes was observed by thermomicroscopy in polarized light. Form A, which is less soluble in absolute ethanol than form B, is the more stable thermodynamically in the temperature range from 25 masculine to 50 degrees C where the data have been obtained. The Van't Hoff diagram layout for each polymorphic form appears to reveal an A<-->B transition temperature in a temperature range lower than 25 degrees C. This study, undertaken as from the research phase, has enabled us to highlight the polymorphism of this new chemical entity by means of XRDP by explaining the nature of the endothermic phenomena observed by DSC, and lastly identify the thermodynamically more stable polymorphic form, thus contributing to a better knowledge of this future drug.

F 12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in New Zealand rabbits fed a casein-enriched diet.

F 12511, a novel ACAT inhibitor, lowers plasma cholesterol levels in New Zealand rabbits fed a cholesterol-free casein-rich diet. In rabbits endogenous hypercholesterolemia pre-established for 8 weeks was used to compare treatments with F 12511 and atorvastatin for a further 8-week period, and to determine whether both agents act synergistically. F 12511 appears to be 3-4-fold more potent than atorvastatin in reducing total plasma cholesterol (active doses ranging from 0.16 to 2.5 and from 1.25 to 10 mg/kg per day, respectively) while the hypocholesterolemic efficacy of both compounds at 2.5 mg/kg per day amounted to 70 and 45%, respectively. A reduction by as much as 75% of esterified cholesterol in liver mediated by F 12511 could account for the decrease of plasma VLDL, LDL and apo B-100, whereas a reduction of the LDL production rate has been described as the main mechanism underlying the atorvastatin effect. F 12511 modified adrenal cholesterol balance only at the largest dose studied. In a further experiment the co-administration of threshold doses of F 12511 and atorvastatin (0.63 and 1.25 mg/kg per day, respectively) lowered plasma total cholesterol and apo B-100 containing lipoproteins to a greater extent and more rapidly than either agent alone. In the liver a decrease by atorvastatin in free cholesterol substrate for ACAT may amplify the effect of F 12511 on cholesteryl ester content leading to a diminution, in at least an additive manner, of the assembly and secretion of atherogenic lipoproteins in New Zealand rabbits which have developed an endogenous hypercholesterolemia. Thus, the combination of the ACAT inhibitor F 12511 with atorvastatin can represent a better approach than either agent alone to regulate lipoprotein metabolism in certain pathophysiological situations.

Pharmacological profile of F 12511, (S)-2',3', 5'-trimethyl-4'-hydroxy-alpha-dodecylthioacetanilide a powerful and systemic acylcoenzyme A: cholesterol acyltransferase inhibitor.

The pharmacological profile of F 12511 (S)-2',3', 5'-trimethyl-4'-hydroxy-alpha-dodecylthio-phenylacetanilide, a new inhibitor of acyl-CoA: cholesterol acyltransferase (EC 2.3.1.26; ACAT), was evaluated by using different in vitro and in vivo models. In vitro, F 12511 was shown to be a highly potent inhibitor of ACAT activity in microsomal preparations from various animal species as well as of cholesterol esterification in relevant human cell lines in culture. The concentrations of F 12511 required to produce 50% inhibition of ACAT activity (IC(50) values) in microsomal preparations ranged from 41nM for hypercholesterolemic rabbit intestine to 223 nM for normocholesterolemic hamster liver. In whole cell assays using hepatic (Hep G2), intestinal (CaCo-2) and macrophagic (THP-1) cell lines, F 12511 inhibited ACAT activity with IC(50) values of 3, 7, and 71 nM, respectively. In vivo, orally administered F 12511 displayed high potency and efficacy as an antihypercholesterolemic compound in different cholesterol-fed animals (rat, guinea-pig, rabbit). For instance, in guinea-pigs the dose required to reduce plasma cholesterol levels by 30% (ED(30) value) was 0.008 mg.kg(-1.) In rabbits, an animal species prone to atherosclerosis, the hypocholesterolemic effect was accompanied by a dose-related reduction in the incidence of aortic fatty streaks that reached asymptote at 2.5 mg.kg(-1) and by an improvement of the impaired endothelial function. When given orally to chow-fed hamsters, F 12511 elicited a dose-related decrease in plasma cholesterol from 9% at 0.63 mg.kg(-1) up to 31% at 40 mg.kg(-1) associated with a preferential reduction in atherogenic lipoproteins, very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Moreover, in the same dose range, F 12511 decreased hepatic cholesteryl ester concentrations and reduced liver ex vivo ACAT activity. By using a bioassay, ACAT inhibitory activity was present in plasma of treated hamsters 1 hr after oral administration of F 12511. Hence, the results in chow-fed hamsters are consistent with systemic and direct hepatic effects of F 12511. In guinea-pigs, an adreno-sensitive species, F 12511 did not impair the adrenal function (adrenocorticotrophic hormone challenge) at doses up to 2.5 mg.kg(-1,) far higher than those eliciting hypocholesterolemic effects in the same species. In conclusion, the results suggest that F 12511, a powerful and systemic ACAT inhibitor, constitutes an appropriate tool to determine whether the inhibition of ACAT constitutes an effective therapy for the treatment of hypercholesterolemia and of atherosclerosis in man.

Characterization of polymorphs and solvates of 3-amino-1-(m-trifluoromethylphenyl)-6-methyl-1H-pyridazin-4-one.

The characterization of two polymorphs of the title compound (F2692; 1) by differential scanning calorimetry (DSC), microanalysis, proton nuclear magnetic resonance spectroscopy, thermogravimetry, thermomicroscopy, infrared spectroscopy, and X-ray diffractometry is described. Both polymorphs are crystalline, with form II being more stable at temperatures less than 160 degrees C. The thermal behavior was studied at different rates of heating, and the enthalpies of transition were calculated from DSC data. The transformation of aqueous suspensions of form I to the water-stable form II is described, and the heats of solution and intrinsic aqueous dissolution rates of both polymorphs were determined. 1 also formed solvates with dimethyl sulfoxide and 1-methyl-2-pyrrolidinone. The solvates were studied by thermogravimetry, DSC, and infrared spectroscopy.

Immediate unilateral tonsillectomy for severe peritonsillar infections in children.

Twenty-four children with severe peritonsillar infections, subjected to unilateral tonsillectomies were studied with regards to the incidence of late infections in the remaining tonsil. Unilateral immediate tonsillectomy is an effective and sufficient treatment for unilateral peritonsillar abscesses in children or adolescents. The removal of the opposite uninvolved tonsil is not justified for it increases the risk of surgical morbidity, deprives the individual of an immunocompetent organ and does not result in demonstrable clinical benefit.